PROJECT SUMMARY/ABSTRACT: BACKGROUND: NIMH-sponsored meetings (2014) and the 1st and 2nd Congresses on Pediatric Irritability (Sept 2015 and 2017) highlighted the critical need for greater understanding of the brain/behavior mechanisms underlying irritability in children? particularly in trans-diagnostic samples of children drawn across the range of irritability, rather than a single DSM disorder. The reason is that irritability and resultant aggression are the most common symptoms for which parents seek psychiatric care for their children (>40% of ED cases, >20% of psychiatric outpatient visits). Childhood irritability is a significant predictor of impairment in adulthood, including psychopathology, suicide, and decreased financial attainment. The career development objectives of this K24 Midcareer Investigator Award in Patient-Oriented Research (POR) are to gain expertise in (1) computational psychiatry techniques including modeling of functional magnetic resonance imaging (fMRI) data; (2) white matter connectivity via diffusion tensor imaging (DTI) and diffusion spectral imaging (DSI), and (3) mentorship in education. The research objectives of this K24 Award are: (1) identify PFC-amygdala-striatal circuit-based clusters of irritability using computational psychiatry modeling of event-related reversal learning fMRI, resting-state fMRI, and diffusion white matter connectivity data, and (2) to develop, pilot, and test a novel tiered mentorship program for imaging-related POR for medical and psychology trainees and early career faculty. My central hypothesis is that all irritability does not result from a single mechanism; rather unique symptom clusters of irritability result from specific PFC-amygdala-striatal circuit alterations mediating cognitive flexibility. The rationale for this K24 proposal is that, at this critical juncture in my career, it will allow me to acquire new imaging and mentorship skills, passing them on to the next generation of clinician/scientists. Research Method: I will test this hypothesis by enrolling a trans-diagnostic sample of n=72 adolescents ages 13-16 years drawn across the range of irritability, while using extant data from children with bipolar disorder and typically-developing controls to initially learn computational psychiatry modeling and DTI analysis methods from my mentors. This K24 is innovative because it will tackle the NIMH-high priority area with cutting-edge imaging techniques, including multi-band fMRI scanning for better temporal resolution of fMRI data, computational psychiatry modeling for better inference/interpretation of these data, and multi-band DTI/DSI scanning that can address prior concerns of difficulty resolving crossing white matter tracts and long scan times. This K24 is significant because it will address the NIMH high-priority area of research on pediatric irritability (NIMH Strategic Plan 1.1 and 1.3), while my plan for mentorship and innovative curricular sharing will help fuel the next generation of clinician/scientists using imaging-related POR to help their patients suffering from neuropsychiatric illness?at Brown and beyond?and for some, engaging themselves in imaging POR.